scholarly journals The structure of a LAIR1-containing human antibody reveals a novel mechanism of antigen recognition

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Fu-Lien Hsieh ◽  
Matthew K Higgins
Keyword(s):  
Immune Cell ◽  
Adaptive Immune System ◽  
Antigen Recognition ◽  
Binding Potential ◽  
Human Antibody ◽  
Antigen Binding ◽  
Antigen Binding Site ◽  
Fab Fragment ◽  
Cell Recruitment ◽  
Critical Components

Antibodies are critical components of the human adaptive immune system, providing versatile scaffolds to display diverse antigen-binding surfaces. Nevertheless, most antibodies have similar architectures, with the variable immunoglobulin domains of the heavy and light chain each providing three hypervariable loops, which are varied to generate diversity. The recent identification of a novel class of antibody in humans from malaria endemic regions of Africa was therefore surprising as one hypervariable loop contains the entire collagen-binding domain of human LAIR1. Here, we present the structure of the Fab fragment of such an antibody. We show that its antigen-binding site has adopted an architecture that positions LAIR1, while itself being occluded. This therefore represents a novel means of antigen recognition, in which the Fab fragment of an antibody acts as an adaptor, linking a human protein insert with antigen-binding potential to the constant antibody regions which mediate immune cell recruitment.

scholarly journals The mycoplasma surface proteins MIB and MIP promote the dissociation of the antibody-antigen interaction

2021 ◽  
Vol 7 (10) ◽  
pp. eabf2403
Author(s):  
Pierre Nottelet ◽  
Laure Bataille ◽  
Geraldine Gourgues ◽  
Robin Anger ◽  
Carole Lartigue ◽  
...  
Keyword(s):  
Surface Proteins ◽  
Mycoplasma Species ◽  
Antigen Binding ◽  
Antigen Binding Site ◽  
Fab Fragment ◽  
Cryo Electron Microscopy ◽  
Antigen Complex ◽  
Antigen Interaction ◽  
Immunoglobulin Binding

Mycoplasma immunoglobulin binding (MIB) and mycoplasma immunoglobulin protease (MIP) are surface proteins found in the majority of mycoplasma species, acting sequentially to capture antibodies and cleave off their VH domains. Cryo–electron microscopy structures show how MIB and MIP bind to a Fab fragment in a “hug of death” mechanism. As a result, the orientation of the VL and VH domains is twisted out of alignment, disrupting the antigen binding site. We also show that MIB-MIP has the ability to promote the dissociation of the antibody-antigen complex. This system is functional in cells and protects mycoplasmas from antibody-mediated agglutination. These results highlight the key role of the MIB-MIP system in immunity evasion by mycoplasmas through an unprecedented mechanism, and open exciting perspectives to use these proteins as potential tools in the antibody field.

scholarly journals Kappa-on-Heavy (KoH) bodies are a distinct class of fully-human antibody-like therapeutic agents with antigen-binding properties

2019 ◽  
Vol 117 (1) ◽  
pp. 292-299 ◽  
Author(s):  
Lynn E. Macdonald ◽  
Karoline A. Meagher ◽  
Matthew C. Franklin ◽  
Natasha Levenkova ◽  
Johanna Hansen ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Pocket ◽  
Human Antibody ◽  
Antigen Binding ◽  
Wild Type ◽  
Antigen Binding Site ◽  
Binding Properties ◽  
Variable Domains ◽  
Constant Domains ◽  
Ig Heavy Chain

We describe a Kappa-on-Heavy (KoH) mouse that produces a class of highly diverse, fully human, antibody-like agents. This mouse was made by replacing the germline variable sequences of both the Ig heavy-chain (IgH) and Ig kappa (IgK) loci with the human IgK germline variable sequences, producing antibody-like molecules with an antigen binding site made up of 2 kappa variable domains. These molecules, named KoH bodies, structurally mimic naturally existing Bence-Jones light-chain dimers in their variable domains and remain wild-type in their antibody constant domains. Unlike artificially diversified, nonimmunoglobulin alternative scaffolds (e.g., DARPins), KoH bodies consist of a configuration of normal Ig scaffolds that undergo natural diversification in B cells. Monoclonal KoH bodies have properties similar to those of conventional antibodies but exhibit an enhanced ability to bind small molecules such as the endogenous cardiotonic steroid marinobufagenin (MBG) and nicotine. A comparison of crystal structures of MBG bound to a KoH Fab versus a conventional Fab showed that the KoH body has a much deeper binding pocket, allowing MBG to be held 4 Å further down into the combining site between the 2 variable domains.

scholarly journals Structure of the Anti-C60 Fullerene Antibody Fab Fragment: Structural Determinants of Fullerene Binding

Acta Naturae ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 58-65 ◽  
Author(s):  
E. M. Osipov ◽  
O. D. Hendrickson ◽  
T. V. Tikhonova ◽  
A. V. Zherdev ◽  
O. N. Solopova ◽  
...  
Keyword(s):  
Binding Site ◽  
Hydrophobic Surface ◽  
Binding Pocket ◽  
C60 Fullerene ◽  
Antigen Binding ◽  
Structural Determinants ◽  
Antigen Binding Site ◽  
Fab Fragment ◽  
X Ray Crystallography ◽  
Solvent Accessible Area

The structure of the anti-C60 fullerene antibody Fab fragment (FabC60) was solved by X-ray crystallography. The computer-aided docking of C60 into the antigen-binding pocket of FabC60 showed that binding of C60 to FabC60 is governed by the enthalpy and entropy; namely, by - stacking interactions with aromatic residues of the antigen-binding site and reduction of the solvent-accessible area of the hydrophobic surface of C60. A fragment of the mobile CDR H3 loop located on the surface of FabC60 interferes with C60 binding in the antigen-binding site, thereby resulting in low antibody affinity for C60. The structure of apo-FabC60 has been deposited with pdbid 6H3H.

scholarly journals Crystal structure of a glycosylated Fab from an IgM cryoglobulin with properties of a natural proteolytic antibody

2006 ◽  
Vol 395 (3) ◽  
pp. 473-481 ◽  
Author(s):  
Paul A. Ramsland ◽  
Simon S. Terzyan ◽  
Gwendolyn Cloud ◽  
Christina R. Bourne ◽  
William Farrugia ◽  
...  
Keyword(s):  
Serine Proteases ◽  
Three Dimensional ◽  
Catalytic Triad ◽  
Dimensional Structure ◽  
Gel Point ◽  
Antigen Binding ◽  
Antigen Binding Site ◽  
Fab Fragment ◽  
Peripheral Tissues ◽  
Fragment Antigen Binding

The 2.6 Å (1 Å=0.1 nm) resolution structure has been determined for the glycosylated Fab (fragment antigen binding) of an IgM (Yvo) obtained from a subject with Waldenström's macroglobulinaemia. Dynamic light scattering was used to estimate the gel point and monitor the formation of an ordered hydroscopic gel of Yvo IgM upon cooling. If a cryoglobulin forms gels in peripheral tissues and organs, the associated swelling and damage to microvasculature can result in considerable morbidity and mortality. The three-dimensional structure of the branched N-linked oligosaccharide associated with the CH1 domain (first constant domain of heavy chain) is reported. The carbohydrate may act to shield part of the lateral surface of the CH1 domain and crowd the junction between the CH1 and CH2 domains, thereby limiting the segmental flexibility of the Fab arms in intact Yvo IgM, especially at low temperatures. Recently, Yvo IgM was shown to have the properties of a naturally occurring proteolytic antibody [Paul, Karle, Planque, Taguchi, Salas, Nishiyama, Handy, Hunter, Edmundson and Hanson (2004) J. Biol. Chem. 279, 39611–39619; Planque, Bangale, Song, Karle, Taguchi, Poindexter, Bick, Edmundson, Nishiyama and Paul (2004) J. Biol Chem. 279, 14024–14032]. The Yvo protein displayed the ability to cleave, by a nucleophilic mechanism, the amide bonds of a variety of serine protease substrates and the gp120 coat protein of HIV. An atypical serine, arginine and glutamate motif is located in the middle of the Yvo antigen-binding site and displays an overall geometry that mimics the classical serine, histidine and aspartate catalytic triad of serine proteases. Our present findings indicate that pre-existing or natural antibodies can utilize at least one novel strategy for the cleavage of peptide bonds.

scholarly journals Antigen clasping by two antigen-binding sites of an exceptionally specific antibody for histone methylation

2016 ◽  
Vol 113 (8) ◽  
pp. 2092-2097 ◽  
Author(s):  
Takamitsu Hattori ◽  
Darson Lai ◽  
Irina S. Dementieva ◽  
Sherwin P. Montaño ◽  
Kohei Kurosawa ◽  
...  
Keyword(s):  
Binding Sites ◽  
High Specificity ◽  
Antigen Recognition ◽  
Antigen Binding ◽  
Modular Architecture ◽  
Antigen Binding Site ◽  
Dimer Interface ◽  
Aromatic Cage ◽  
Lysine Residues ◽  
Exquisite Specificity

Antibodies have a well-established modular architecture wherein the antigen-binding site residing in the antigen-binding fragment (Fab or Fv) is an autonomous and complete unit for antigen recognition. Here, we describe antibodies departing from this paradigm. We developed recombinant antibodies to trimethylated lysine residues on histone H3, important epigenetic marks and challenging targets for molecular recognition. Quantitative characterization demonstrated their exquisite specificity and high affinity, and they performed well in common epigenetics applications. Surprisingly, crystal structures and biophysical analyses revealed that two antigen-binding sites of these antibodies form a head-to-head dimer and cooperatively recognize the antigen in the dimer interface. This “antigen clasping” produced an expansive interface where trimethylated Lys bound to an unusually extensive aromatic cage in one Fab and the histone N terminus to a pocket in the other, thereby rationalizing the high specificity. A long-neck antibody format with a long linker between the antigen-binding module and the Fc region facilitated antigen clasping and achieved both high specificity and high potency. Antigen clasping substantially expands the paradigm of antibody–antigen recognition and suggests a strategy for developing extremely specific antibodies.

scholarly journals Simultaneous Expression of Th1- and Treg-Associated Chemokine Genes and CD4+, CD8+, and Foxp3+ Cells in the Premalignant Lesions of 4NQO-Induced Mouse Tongue Tumorigenesis

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1835
Author(s):  
Hana Yamaguchi ◽  
Miki Hiroi ◽  
Kazumasa Mori ◽  
Ryosuke Ushio ◽  
Ari Matsumoto ◽  
...  
Keyword(s):  
Immune Cell ◽  
Tongue Cancer ◽  
Immunohistochemical Analysis ◽  
Premalignant Lesions ◽  
Cytokine Gene Expression ◽  
Cell Infiltration ◽  
Mrna Levels ◽  
Cell Recruitment ◽  
T Cell Infiltration ◽  
Immunohistochemical Analyses

Chemokines and cytokines in the tumor microenvironment influence immune cell infiltration and activation. To elucidate their role in immune cell recruitment during oral cancer development, we generated a mouse tongue cancer model using the carcinogen 4-nitroquinoline 1-oxide (4NQO) and investigated the carcinogenetic process and chemokine/cytokine gene expression kinetics in the mouse tongue. C57/BL6 mice were administered 4NQO in drinking water, after which tongues were dissected at 16 and 28 weeks and subjected to analysis using the RT2 Profiler PCR Array, qRT-PCR, and pathologic and immunohistochemical analyses. We found that Th1-associated chemokine/cytokine (Cxcl9, Cxcl10, Ccl5, and Ifng) and Treg-associated chemokine/cytokine (Ccl17, Ccl22, and Il10) mRNA levels were simultaneously increased in premalignant lesions of 4NQO-treated mice at 16 weeks. Additionally, although levels of Gata3, a Th2 marker, were not upregulated, those of Cxcr3, Ccr4, and Foxp3 were upregulated in the tongue tissue. Furthermore, immunohistochemical analysis confirmed the infiltration of CD4+, CD8+, and Foxp3+ cells in the tongue tissue of 4NQO-treated mice, as well as significant correlations between Th1- or Treg-associated chemokine/cytokine mRNA expression and T cell infiltration. These results indicate that CD4+, CD8+, and Foxp3+ cells were simultaneously recruited through the expression of Th1- and Treg-associated chemokines in premalignant lesions of 4NQO-induced mouse tongue tissue.

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